Clinical trial attitudes among individuals with Alpha-1 antitrypsin deficiency

Aim:To evaluate all-cause and liver-associated healthcare resource utilization (HCRU) and costs among patients with alpha-1 antitrypsin deficiency (AATD) with liver disease (LD) and/or lung disease (LgD).Materials & methods:This was a retrospective analysis of linked administrative claims data from the IQVIA PharMetrics® Plus and the IQVIA Ambulatory Electronic Medical Records (AEMR) databases from 1 July 2021 to 31 January 2022. Patients with AATD in the IQVIA PharMetrics Plus database were included with ≥1 inpatient or ≥2 outpatient medical claims ≥90 days apart with a diagnosis of AATD, or with records indicating a protease inhibitor (Pi)*ZZ/Pi*MZ genotype in the IQVIA AEMR database with linkage to IQVIA PharMetrics Plus. For a patient's identified continuous enrollment period, patient time was assigned to health states based on the initial encounter with an LD/LgD diagnosis. A unique index date was defined for each health state, and HCRU and costs were calculated per person-year (PPY).Results:Overall, 5136 adult and pediatric patients from the IQVIA PharMetrics Plus and IQVIA AEMR databases were analyzed. All-cause and liver-associated HCRU and costs were substantially higher following onset of LD/LgD. All-cause cost PPY ranged from US $11,877 in the absence of either LD/LgD to US $74,015 in the presence of both LD and LgD. Among liver transplant recipients in the AATD with LD health state, liver-associated total costs PPY were US $87,329 1-year pre-transplantation and US $461,752 1-year post-transplantation. In the AATD with LgD and AATD with LD and LgD health states, patients who received augmentation therapy were associated with higher all-cause total costs PPY and lower liver-associated total costs PPY than their counterparts who did not receive augmentation therapy.Conclusion:Patients with AATD had increased HCRU and healthcare costs in the presence of LD and/or LgD. HCRU and healthcare costs were highest in the AATD with LD and LgD health state.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic interstitial lung disease characterized by progressive lung scarring and the pathological hallmark of usual interstitial pneumonia (UIP). On the other hand, Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder predisposing individuals to lung and liver diseases. Despite its rarity in literature, the relationship between IPF and AATD remains unclear. While IPF often necessitates lung transplantation in advanced stages, traditional AATD management involves supportive therapy. However, the introduction of supplemental alpha1-antitrypsin (AAT) derived from pooled human plasma has shown promise in retarding lung function decline. Notably, post lung transplantation, the genetic basis of AATD-related lung disease persists, potentially exposing patients to disease recurrence. Here, we present a clinical case of a patient initially diagnosed with IPF who subsequently underwent double lung transplantation and was later diagnosed with AATD. This case study prompts inquiry into critical unresolved questions: the potential benefits of post-transplant augmentation therapy for AATD patients and the potential association between AATD and pulmonary fibrosis. The intricate interplay between these two conditions underscores the need for further investigation to enhance our understanding and improve patient outcomes

Alpha-1 antitrypsin (AAT) augmentation therapy is the only specific treatment available for alpha-1 antitrypsin deficiency (AATD) related lung disease. Randomised control trials (RCTs) have consistently demonstrated its benefit in preserving lung density as measured with CT densitometry. These studies were not adequately powered to detect differences in mortality or progression to lung transplant. Use of retrospective data may provide insight into effects of augmentation on survival and progression to lung transplant. Comparison was made between augmentation naive AATD patients from the AATD UK registry (UK) and patients on augmentation therapy followed up in AlphaNet’s Disease Management and Prevention Program in the US. Kaplan-Meier survival analysis of 1535 adult patients with severe AATD and associated lung disease was performed with matching for age, sex and smoking status. Time to death or lung transplant was taken from start of augmentation (treatment) or baseline assessment (control). Estimated mean survival was significantly longer in the treatment group: augmentation 20.3 years (95%CI 19.4 to 21.2), control 13.7 years (95%CI 13.1 to 14.3) p This study suggests treatment with augmentation therapy prolongs survival or time to lung transplantation compared to those who are augmentation naive and should be considered for AATD patients with lung disease.

Rationale: Alpha-1 antitrypsin deficiency (AATD), an under-recognized genetic condition, can cause chronic obstructive pulmonary disease (COPD) and/or liver disease in adults. Symptoms of individuals who have COPD and/or liver disease due to AATD are often indistinguishable from those without deficiency, necessitating additional tools to establish diagnosis. Using claims data from the large United States Komodo Health database, we previously reported an artificial intelligence model to identify symptomatic patients who likely had AATD but were unrecognized. In this current study, we used retrospective deidentified patient data generated from the Cleveland Clinic Electronic Medical Record (EMR) to define and characterize patient cohorts utilized to calibrate and refine the model. Methods: Data from deidentified patient records, sourced from the Cleveland Clinic EMR between January 1, 1998 and August 15, 2024, were analyzed. Patients who had positive AATD diagnoses were grouped into categories depending upon how diagnoses were confirmed (genetic: genotype confirming AATD; severe: severe deficiency in AAT serum levels [<57 mg/dL]; and mild: mild deficiency in AAT serum levels [57-90 mg/dL]). Clinical phenotype and treatment patterns for these subgroups were analyzed based on the presence of relevant medical codes in patients’ records. Results: Of 794 patients with AATD, 290 patients (36.5%) were identified by genotype (genetic), the remaining patients were characterized by serum AAT level in the severe (n=117, 14.7%) and mild (n=387, 48.7%) categories. Overall, 50.4% of patients were male; median age was 63 years. Prevalence of common comorbidities was lower in the mild subgroup versus the total population and other subgroups: COPD (total: 40.1%, genetic: 44.8%, severe: 47.9%, mild: 34.1%), unspecified liver disease (total: 34.9%, genetic: 41.4%, severe: 40.2%, mild: 28.4%), and emphysema (total: 31.7%, genetic: 36.9%, severe: 38.5%, mild: 25.8%). Overall, 12.5% of patients had any AATD augmentation therapy drug in their records. When assessed by subgroup, 22.4% of the genetic group, 17.9% of the severe group, and 3.4% of the mild group had an augmentation therapy drug listed in their records; patients with emphysema had higher rates of receiving augmentation therapy than patients without (Figure 1). Conclusions: Within the Cleveland Clinic EMR, this analysis identified phenotypic and treatment pattern differences among cohorts of patients confirmed to have AATD. Lower frequencies of comorbidities, as well as lower rates of patients who received augmentation therapy for AATD, were observed in patients with mild deficiency of AAT compared with patients with confirmed genetic diagnoses and those with severe deficiency of AAT.

Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition that predisposes patients to lung and liver disease and is often underdiagnosed due to incomplete diagnosis of chronic obstructive pulmonary disease (COPD) and asthma. Improvements in physician awareness have been made, but better strategies for both diagnosis and management are still required. The only current disease-modifying therapy for AATD is the infusion of the missing Alpha-1 Antitrypsin (AAT) protein, which can slow progression of emphysema. However, AAT treatment can impact patient freedom and quality of life due to the need for weekly intravenous infusions. A symposium was held to discuss patient-centric aspects of care that have impact on the lives of patients with AATD, including exacerbations of their lung disease, self-administration of intravenous AAT therapy and pulmonary rehabilitation. Intravenous self-infusion of drugs is an established treatment strategy for patients with a variety of conditions and can improve patient quality of life, freedom and mental well-being. Experience from these areas show that patients typically manage their treatment well and without complications. When applied to AATD, training patients to self-infuse therapy can be successful, but formal guidelines would be beneficial. In addition to pharmacological intervention, individualized pulmonary rehabilitation, exercise and educational programs can encourage health-enhancing patient behavior and further improve patient quality of life. However, differences in skeletal muscle adaptations to pulmonary rehabilitation exercise regimens have been observed between patients with AATD and non-AATD COPD, highlighting the need to develop training programs specifically designed for patients with AATD.

Alpha-1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5-methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early-stage AATD and the ZZ genotype, genome-wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver-impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome-wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well-known sex-specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland.Clinical demographics and available thoracic computerised tomography (CT) imaging were detected from 139 PiZZ individuals identified from the Irish National AATD Registry. Clinical information was collected by questionnaire. Data was analysed to assess AATD disease severity and evaluate predictors of clinical phenotype.Questionnaires were collected from 107/139 (77%) and thoracic CT evaluation was available in 72/107 (67.2%). 74% of respondents had severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stage C or D). Cigarette smoking was the greatest predictor of impairment in FEV1 and DLCO (%predicted) and the extent of emphysema correlated most significantly with DLCO. Interestingly the rate of FEV1 decline was similar in ex-smokers when compared to never-smokers. Passive smoke exposure in childhood resulted in a greater total pack-year smoking history. Radiological evidence of bronchiectasis was a common finding and associated with increasing age.The Irish National AATD Registry facilitates clinical and basic science research of this condition in Ireland. This study illustrates the detrimental effect of smoke exposure on the clinical phenotype of AATD in Ireland and the benefit of immediate smoking cessation at any stage of lung disease.

Introduction: Based on limited studies, it has been proposed that alpha-1 antitrypsin deficiency (A1ATD) is associated with a risk of primary hepatocellular carcinoma (HCC) that exceeds that attributable to cirrhosis alone. Moreover, recent data suggest that PI*Z heterozygotes (e.g., PI*MZ) had an increased risk of HCC. The aim of this study was to evaluate the association between A1ATD/ Z allele and HCC in a cohort of patients with end stage liver disease (ESLD). Methods: Patients evaluated for orthotopic liver transplant at the Cleveland clinic between 2003 and 2014 were included in this retrospective study. Complete data was collected on 696 subjects. The diagnosis of A1ATD was based on phenotype abnormalities (ZZ or MZ), the presence of PAS-positive diastaseresistant (PAS+) globules on liver biopsy, or both. The diagnosis of HCC was based on imaging, biopsy, or examination of the explanted liver. All patients with A1ATD were identified and the prevalence of HCC in this population was calculated. Time-to-event analysis for interval censored data was performed to assess occurrence of HCC in patients with other causes of cirrhosis such as alcoholic liver disease, hepatitis C (HCV), or non-alcoholic steatohepatitis (NASH). Results: A total of 696 subjects were included in the analysis. Seven percent of these had A1ATD. Of subjects without A1ATD, 45% had HCV, 18% had alcoholic liver disease, 18% had NASH, and 18% had other primary diagnosis. Median follow-up time was 3.2 years (25th, 75th percentiles: 1, 5.2), during which time 29% of subjects developed HCC. Crude percentage of HCC was 8.5% in the A1ATD group compared to 30% in the no A1ATD group (p=0.004). Figure 1 presents the cumulative incidence plot for HCC. Subjects with A1ATD were found to have significantly lower HCC rates compared to subjects without A1ATD (p=0.002).Figure 1: Cumulative incidence of HCC in ESLD patients with and without A1ATD.Conclusion: A1ATD was not associated with an increased risk of HCC in a group of patients with ESLD. In fact, patients with cirrhosis and A1ATD were less likely to develop HCC compared to patients with other causes of cirrhosis.

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition classically associated with pulmonary emphysema and liver disease. However, the potential link between AATD and other respiratory diseases, particularly bronchial asthma, remains poorly understood and highly debated. This narrative review explores the current evidence regarding the epidemiological, clinical, and pathophysiological relationship between AATD and asthma. Data from prevalence studies show marked variability in the frequency of AATD-associated alleles among asthma patients, ranging from 2.9% to 25.4%, suggesting either a true association or selection biases. Conversely, asthma prevalence among AATD patients also varies widely, from 1.4% to 44.6%, with higher frequencies observed in countries with long-standing national registries. However, methodological inconsistencies and a lack of standardized diagnostic criteria limit the interpretation of these findings. Current evidence is insufficient to support a direct causal role for AATD mutations in asthma development, and no clear impact of AATD on asthma severity or prognosis has been established. Furthermore, there is no conclusive evidence that augmentation therapy is beneficial in asthma patients carrying AATD mutations. Despite these uncertainties, screening for AATD in selected asthma populations—especially those with severe or atypical phenotypes—may be warranted, as recommended by major respiratory societies. Future research should focus on large, well-powered, prospective studies that evaluate the potential pathophysiological interactions between AATD and specific asthma endotypes, particularly T2-low asthma. These efforts may help clarify the relevance of AATD mutations in asthma pathogenesis and identify potential therapeutic targets.

Background The benefits of pulmonary rehabilitation (PR) on fatigue-resistant skeletal muscle fibre type I have been found to be smaller in COPD patients with alpha-1 antitrypsin deficiency (AATD) than in those without AATD. Alpha-1 antitrypsin (AAT) augmentation therapy was suggested as a potential factor of influence. Whether this finding mirrors different improvements in 6-min walk distance (6MWD) between both groups remains unknown. Methods 140 patients with AATD-related COPD (phenotype PiZZ, FEV 1 : 31 ± 8%pred.) and 280 COPD patients without AATD (FEV 1 : 31 ± 8%pred.) were matched for baseline 6MWD and included in a retrospective analysis. AATD patients were divided into those “on” (AATD AUG+ ) or “off” (AATD AUG- ) augmentation therapy. 6MWD was assessed pre and post an inpatient 4-week PR program. Plasma level of creatinine was analysed at baseline. Results In AATD and COPD patients with comparable initial 6MWD (331 ± 106 m and 326 ± 101 m, p = n.s.), improvements in 6MWD following PR were similar (+49 ± 49 m and +53 ± 52 m, intra-group change: p AUG+ : +51 ± 55 m, AATD AUG- : +47 ± 40 m, p = n.s.). Only in AATD group, higher baseline creatinine levels and lower 6MWD were positive predictors for the PR-related increase in 6MWD. Conclusions Independently of the genetic variant of AAT, COPD patients achieved the same training-related benefit in 6MWD. Augmentation therapy showed no effect on 6MWD adaptation during PR.

Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of pulmonary emphysema and liver disease. The growing interest in this deficiency in Spain led to the development of the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency (REDAAT) in 1993. At present, the REDAAT is a network of more than 350 health care professionals and the database includes a total of 511 individuals. The adult population included consists of 469 individuals (91.8% of the total) and their phenotype distribution is: 348 Pi*ZZ (74.2%), 100 Pi*SZ (21.3%) and 21 carriers of rare variants (4.5%). The most frequent diagnosis is lung disease (74.6%). Patients with chronic obstructive pulmonary disease (COPD) registered in the REDAAT constitute approximately 15% of the expected cases of AATD-related COPD in Spain. Pi*ZZ showed more severe impairment in lung function and younger age at baseline compared with Pi*SZ. The mean decline in FEV1 in the Pi*ZZ subgroup was –23 ml/year (SD:142.8), being –18 ml/year (SD:108.8) in Pi*SZ. Forty-five percent of the Pi*ZZ individuals received augmentation therapy. A total of 61 deaths was recorded.The characteristics of the REDAAT population demonstrate some differential trends compared to other series: distribution of phenotypes, inclusion of children and patients treated with replacement therapy. Patients with the Pi*SZ phenotype were older and had milder lung function impairment. The most important challenge of this registry is to collect good quality long-term data that will allow better understanding of the natural history of the disease in real life.

The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart–Lung Transplant Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant

ENDOBRONCHIAL VALVE TREATMENT OF SEVERE EMPHYSEMA IN PATIENTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY

Rolls Royce for everybody? Diagnosing liver disease by mini-laparoscopy